PROJECT SUMMARY/ABSTRACT Our proposal responds to Notice of Special Interest (NOT-AG-20-008), `Alzheimer's-focused administrative supplements for NIH grants that are not focused on Alzheimer's Disease'. Our current parent grant: R01 NR017431 (PI: Barcellos) `ICLIC-MS for Enhancing Outcomes Research and Clinical Care in Multiple Sclerosis (MS) is currently funding the construction of an ethnically diverse 3,000 MS patient cohort with comprehensive electronic health record (EHR), genetic, environmental exposure, and both longitudinal cognitive and physical disability assessments. This unique cohort is nested within the 4.4 million Kaiser Permanente Northern California (KPNC) Health Plan membership. We will leverage data and biospecimens collected from 3,000 cohort members, along with resources from the well-established KPNC MS Research Program (PI: Barcellos) and 25 years of comprehensive EHR and pharmacy data from 2.6 million KPNC members to pursue the proposed investigation which describes three pilot studies to further our understanding of the important relationship between MS and Alzheimer's Disease and Related Dementias (ADRD). Major knowledge gaps on this topic exist and several research priorities have emerged that will be addressed in the proposed investigation. Results from this proposal will lay the foundation for future R01-funded research: We will: 1) characterize the distribution and risk of ADRD in a population representative cohort and sample of MS cases and controls; 2) determine whether APOE-E4, polygenic risk of ADRD, and/or plasma biomarkers of ADRD are associated with cognitive impairment in MS; and 3) investigate the role of DNA methylation aging and rare AD variants in MS cases with ADRD. An improved understanding of shared risk factors and underlying biology of both MS and ADRD will help guide future treatment strategies as well as provide mechanistic insight into how MS and ADRD might develop in the same individual.